Manufacture of thiazolidine derivatives



. tion following hereafter.

Patented Febi 1939 I MANUFACTURE OF THIAZOLIDINE DERIVATIVES Walter Maier, Jessnitz in Anhalt, Germany, asslgnor to I. G. Farbenindustrie Aktiengesellschalt, Franktort-on-the-Main, Germany No Drawing. Application June 2, 1936, Serial No. 83,167. In Germany June 8, 1935 19 Claims. (01. 266-302) My present invention rlatesto the manufacture of thiazolidine derivatives.

One of its objects is a process ot'manuiacturin;' new thiazolidine derivatives. Other objects are the new thiazolidine derivatives. Further objects will be seen from the detailed speciflcasame result.

It is known to convert carbon bisulfide, phenylated mustard oil and thioacetamide into thiazothe nitrogen atom of the thiazolidine nucleus because the reaction of the mercapto thiazolidine ether with 1 molecular proportion of cyclic imine leads to compounds which have the same properties and the analysis of which leads to the 5 Ingeneral the reaction oi 1 molecular proportion of xanthogenate with 1 molecular proportion of cyclic imine gives the best yield, of mercapto line derivatives by interaction with cyclic imines. thiazolidine ether if 1 molecular proportion of According to this invention it has been found xanthogenate is reacted with 1 molecular proporthat under certain conditions xanthogenates or tion of cyclic imine and 1 molecular proportion the corresponding xanthogeni'c acids may be reof an optional acid (formation of a salt of the acted with cyclic imines, however, the nature oi' cyclic imine). If 1 molecular proportion of xan the reaction is difl'erent from that above specified thogenate is reacted with 2 molecular proportions l5 because there are not obtained products of the of cyclic imine, the best yield will be obtained 11 type of unsaturated thiazolines but compounds 1 molecular proportion of xanthogenate is reoi' the type of the saturated thiazolidine. These acted with 2 molecular proportions ot cyclic imine products contain a mercapto group which. is easily and 1 molecular proportion of an optional acid. capable of further reaction. The products which The same compounds are also obtained in a reare produced-by the interaction of one molecular action with two separate stagesif at first 1 moproportion of ethylene imine and one molecular lecular proportion of xanthogenate is reacted P oportion of xanthogenate or of the correspondwith 1 molecular proportion of imine and the ing xanthogenic acid are on account of their resulting mercapto thiazolidine ether i1 desired properties and the analyses made from these after isolation is reacted with afurther molecular products probably Z-mercapto-thiazolidines at the proportion of a cyclic imine whereby thepbest 2-position or which there is linked in ether-like yield will be obtained when the imine is applied in the radical of the used xanthogenate: as the free base.

S OER S J With other conditions of alkalinity or acidity CHR K the reaction likewise sets in, however, mostly a 11.01 l 11.0.0 considerable reduction of the yield with relation s11 NR|-- HR, 7 NR, to the expected compound occurs. This is essen- 11 tially the case it a strong acid or a strong base wherein R stands for a substituted or unsub-sm is present in a greater excess whereby the term tuted, saturated or unsaturated aliphatic, arog z base" m i for matic, h droaromati r 115 93109, 9309550 Y c and y c o hetemcycnc radical Instead of the pure cyclic imine there also R1 stands for H or a substituted or unsubstitu be used solutions which lead to the produc on o saturated .or unsaturated aliphatic, aromaffi the imine and contain beides the mine for hydroaromatlc or heterocyclic radical, a stance common salt, that 1s to say raw solutions 40 R: and R3 stand for H ,or halogen, carboxyl, of technical purity contaimng imine- Further a sulfo group, alkyl acy] cycloalkyl My] or more it has been found that the conversion 01' aralkyl. I the xanthogenates under certain conditions may J be performed directly with the starting materials If there are used for the reaction two or more from which the cyclic imines are produced such molecular proportions of cyclic imine, there' are as halo n lkyl m n 1 amln lkyl l 8111! obtained under certain conditions compounds esters of the formula which on one molecular proportion oi' xantho- H genate contain 2 molecular proportions of the cyclic imine. The second molecular proportion of cyclic imine has probably entered the molel cule of the mercapto thiazolidine ether built in -n a first reaction from the xanthogenate and the first molecule of the cyclic imine in form 01' an 7 \R aminoalkyl radical which is probably linked to B 'is the basis of the applied xanthogenate.

in which R1, R2 and R3 stand for the same radicals as those specified for the formula on page l, and the like compounds. Attention must be paid in this case to the above lines of direction according to which for a good yield one molecular proportion of free cyclic imine base has to be replaced byone molecular proportion of the corresponding .halogenalkylamine base'plus one molecular proportion of NaOH or by one molecular proportion of an aminoalkylol suIfo ester plus 2 molecular proportions of NaOH.

The temperature of the reaction is selected in accordance with the sensitiveness of the xanthogenate against temperature and in accordance with the properties of the nuclear imine or the halogenalkylamine which is brought to reaction. Generally it can be said that the imines react already at ordinary temperature very quickly. The chloralkylamines react sumciently quick at a temperature of 40 C. and higher up to 100 C. or even higher according to the used solvent whereas the bromalkylamines as totheir reactivity lie between the imines and the chloralkylamines. Of course the duration of the reaction and thetemperature at which the reaction is carried out may be varied with respect to each other.

The reaction is preferably carried out in aqueous or alcoholic solution or with the use of a mixture of water and alcohol as a solvent, where- 'by, if a rexanthogenation shall be avoided, the

used alcohol must be the same as that which As cyclic imines there are suitable besides ethyleneimine and its products of substitution such as ethylene-imine,-2-carboxylic acid, ethylene-imine sulfonic acid, furthermore C-alkyl-, acyl-, cycloalkyl-, aryl-, or aralkyl products of substitution such as N-methylethylen'e-imine, 2-3-diacetyiethylene-imine, 2-octadecylethylene-imine, N-

cyclohexanolethylene-imine, 2-phenylethyleneimine, N-propyl-2-viny1-ethylene-imine and analogous products of substitution.

As halogenalkylamines there may be used all 11-2-halogenalkylamines and their products of substitution of the above mentioned kind, whereby the position 1-2- indicates only the neighborhood of the halogen and the amino group and not exclusively the terminal position, for instance,

bromethylamine, N methyl bromethylamine, chlorpropylamine l 2 chlorpropylamine-Z-l,

brombutylamine-2-3 and N-butylchlorethylamine. Dichlordiethylamine, N-diethylchlorethylamine, N-vinyl 2 octadecycl chlorethylamine, trijodtriethylamine, N-diethylchlorethylamine and. other halogenamines may be used to introduce an alkylamine radical into the thiazolidine. Instead of the halogenesters it is also possible -to use the sulfoesters or others esters, for instance ethanolaminesulfoesters.

Principally any xanthogenate may be used for the reaction, for instance'methylxanthogenate,

The following examples serve to illustrate the I invention: 4

Example 1.--l30 grams of methylxanthogenate are dissolved in 300 cc. of methanol and the solution is mixed with one of 53 cc. of ethyleneimine and 62 cc. of glacial acetic acid in 300 cc. of

water. With development of heat there separates immediately a heavy oil, the quantity of 'By boiling .the alkaline solution of the oil 2- mercaptothiazollne of the formula S*-CH1 of melting point 170 C. is produced.

Example 2.--30 cc. of a methanolic solution of 0.1 mol. of methylxanthogenate are added to a 1 mixture of 5.7 grams of'N-methylethylene-imine,

30 cc. of water and 5 grams of sulfuric acid.

Immediate development of heat occurs and a heavy, bright yellow oil separates which, in purifled condition. gives analytical values corresponding with N-methyl-2-mercaptothiazolidine-2- methyl ether having the following formula,

, S-CH:

CHz-O-C SH N Hz Example 3.0.37 kilo of octadecylxanthogenate, dissolved in 5 liters of waters, are ,mixed with a solution of 0.1 kilo of ethylene-imine acetate in 1 liter of water. Immediate precipitation of the following compound follows:

, Example 4.-5 grams of bornylxanthogenate are dissolved in 100 cc. of water and the solution is mixed with an aqeous solution of ethyleneimine sulfate. There is immediately" formed a precipitate of resinous behaviour which contains 4.5 per cent of nitrogen in a dry condition.

Example 5.Unripened cellulose xanthogenate solution is stirred with water to form a thin liquid; it is then neutralized tophenolphthalein by means of acetic acid and there is added an aqueous solution of ethylene-imine acetate. There is immediately produced a white, flocculene precipitate of 2-mercaptothiazolidine 2-cellulose ether corresponding with the formula S -GH:

,Cell0C s H NH- Hz (Cell representing the cellulose molecule).

In the presence of about 40 xanthogenate residues per 100 cellulose (Is-molecules in the viscose there is produced a cellulose product having about 2.5 per cent of nitrogen, and 12 per cent ofsulfur.

precipitation is procured by adding a solution of 20 cc. of ethylene-imine and 27 cc. of acetic acid in 300 cc. of water. neously produced contains 5 per cent. of nitrogen after it has been rinsed with water, the water has been separated by means of hot acetone and the product hasbeen dried. Such artificial masses may be dyed with acid dyestufls.

Example 7.22 grams of polyvinyl alcohol are I made into..a paste with a solution of 30 grams of causticsoda solution in 150 cc. of water, '76 cc. of carbon bisulfide are added and the whole is shaken mechanically for 8 hours. After addition of 500 cc. of water the whole is neutralized with about 180 cc. of acetic acid of per cent strength, filtered from any separated sulfur which may be present and the clear solution is mixed with a solution of 30 cc. of ethyleneimine and 40 cc. of glacial acetic acid in 300 cc. of water. There is immediately precipitated a spongy mass containing about 6* per cent of nitrogen. The formula of the resultant com pound may be assumed to be as follows:

. weekly acid solution-of potassium xanthogenate there are added 40 cc. of pure ethylene-imine while continuously and thoroughly stirring. The product of reactionis immediately precipitated in form of a white tough mass.

Example 9.205 grams of bromethylamine bromhydrate are dissolved in a solution of 40 grams of NaOH in 400 cc. of water, and to this of the analysis of the oil indicates the compound to be a mercaptothia zolidine methylether, of the following formula produced by this reaction s NH-C H,

-' Example 10.;--116 grams of chlorethylamine The precipitate instantasolution there are added 130 grams of Na-' This mixture is heated at 55 C. for

K-ethylxanthogenate dissolved in 300 cc. of ethanol are used instead ofthe Na-methylxanthogenate. The oilwhich is obtained shows on analysis the values of the ethyl mercaptothiazolidine ethyl ether. The reaction occurs as fol- Example 12.30 grams of potato starch are dissolved in 100 cc. of water containing 8 grams of NaOH and after addition of '30 cc. of car- 'bon bisu'lflde heated for two hours. After the addition of 500 cc. of water dilute acetic acid is added for neutralization and then the thickly liquid mass is mixed with 1% liter of water of 60 C. in which shortly before the addition there have been dissolved 205 grams of bromethylamine bromhydrate and 40 grams of NaOH. After a short period of time the product of reaction is precipitated. in the form' of flakes.

Example 13.To a solution of 100 grams of sodiummethylxanthogenate dissolved in 300 cc. of methanol there is added a solution heated at 80 C. of 125 grams df aminoethanol sulfoester and 125 grams of NaOH in 500 cc. of water and the mixture is kept for 2 hours at 70-80 C. The thickly liquid oil which is precipitated on cooling and has a brownish color may be purified as described in Example 9. The product has the following formula:

Example 14.151 grams of mercaptothiazolidine methyl ether are dissolved in a mixture of 400 cc. of water, 400 cc. of methanol and 40 grams of NaOH at room temperature, and this solution is mixed with a solution of 205 grams of bromethylamine bromhydrate dissolved in 300 cc. of water which contains 40 grams of NaOH. After a one hour's heating at 40 to 50 C. the mixture is diluted with 500 cc. of water, and the formed heavy oil is separated by means of a separating funnel. By heating the oil for one hour at 80 C. in a vacuum the oil is freed from water and methanol. on cooling the oil assumes a tough condition. The analysis shows that one molecular proportion of mercaptothiazolidine methyl ether are united with one'molecular proportion of the radical CzHsN.

Example 15.-151 grams of mercaptothiazolidine methyl ether are dissolved in 200 cc. oi"

methanol and this solution is added to a solution of 116 grams of chlorethylamine chlorhvdrate 'yields 14.2 per cent of N and 32.8 per cent of S whereas the calculation for CeHuONflS: yields 14.4 per cent of N and 33.0 per cent of S.

Example '16.-The reaction is the same as in Example 15, but with the difference that instead of 80 grams of NaOH there are used 160 grams of NaOH. After the reaction is finished, a solutionof 45 cc. of sulfuric acid dissolved in 500 cc. of water is added and the oil which separates is worked up as described in the preceding example. The product shows the same values of analysis as the compound described in Example After the reaction is finished a solution of 80 grams of NaOH in 500 cc. of water is added and the formed oil is separated. The purified product contains 12.5 per cent of N and 37.4 per cent of S. I

Example 19.-165 grams of mercaptothiazolidine ethyl ether are dissolved in 300 cc. of methanol and this solution is mixed with a solution of 130 grams .of methylchlorethylamine chlorhydrate of the formula E C/H:CH:-NH

c1 H 01 and grams of NaOH in 500 cc. of water. After a one hour's heating under reflux at C. the mixture is diluted with 2 liters of water, cooled and the formed oil separated. Afterthe usual working up a. tough oil is obtained which contains 12.5 per cent of N and 28.4 per cent of S whereas the calculation for the compound CzHwONzSz yields 12.6 per cent of N and 28.8

per cent of S.

Example '20.172 grams of diethylchlorethylamine chlorhydrate are dissolved in 300 cc. of methanol and this solution is mixed with a solution of 80 grams of NaOH in 400 cc. of water. To this mixture there is added a solution of 151 rams of mercaptothiazolidine methyl ether in 200 cc. of methanol, and the mixture is heated ethylene-imine in 200 cc. of water. After heating for 30 minutes at 60 C. under reflux-,there are added 300 cc. of water and the mixture is cooled. The oil which is-separated is washed with 300* cc. of water and freed-from water and methanol by heating for 1 hour at 100 C. in a vacuum. The obtained mass which after cooling is tough contains 14.4 per cent of N. I

Example 22,-151 grams of mercaptothiazolidine methyl ether are dissolved in a mixture of 400 cc. of water, 400 cc. of methanol and 40 ams of NaOH at 20 C. and this solution is mixed with a solution of 91 grams of methylethylene-imine acetatein 300 cc. of water. The mixture is allowed to stand over night at room temperature and is diluted with 500 cc. of water, and the formed oil is worked up as described above. There is obtained a tough oil containing 13.6 per cent of N and 30.6 per cent of S; the calculation for the compound C7H1aON2S2 Yields 13.5 per cent of N and 30.8 per cent of S.

Example 23.--205 grams of bromethylamine bromhydrate dissolved in 600' grams of a 20 per 7 cent solution of sodium hydroxide are mixed with 1 hour at 80 C. in a vacuum for removal of the dissolved water or methanol. The colorless mass which is tough when cold contains 14.2 per cent of N and 33.4 per cent of S whereas-the compound CcHmONzSz contains 14.4 per cent of N and 33.0 per cent of S. 7 Example 24.-116 grams of chlorethylamin chlorhydrate dissolved in 800 grams of a 20 per cent solution of sodium hydroxide are mixed with a solution of 80 grams of methylxanthogenate in 200 cc. of methanal and the mixture'is kept for 4 hours at (SO-70 C. After the addition of 500 cc. of water, the oil which separates is worked up as described in Example 28. The tough all contains 12.4 per cent of N and 36.2 per cent of S.

Example 25.144 grams of ethylanthogenate dissolved in 200 cc. of water are mixed with a solution of 43 grams of ethylene-imine, 261 grams of diethylbromethylamine bromhydrate and 120 grams of NaOH in 1000 cc. of water and heatedto 60 C. After one hour the mixture is worked up as described in Example 23. The tough oil which is obtained contains 10.2 per cent of N and 25.7 per cent of S, whereas the compound CuH24ON2Sz contains" 10.6 per cent of, N and. 24.2 per cent of S. Example 26.-- grams of methylxanthogenate dissolved in 200 cc. of methanol are mixed with a solution of 205 grams of bromethylainine bromhydrate and 80 grams of NaOH in 800 cc. of water and after a short time this mixture is mixed with a solution of 5'7 grams of methylethylene-imine in I 200 cc. of water. The mixture which on account of the reaction which takes place has heated itseli at 50 C. is kept at this temperature for further 30 minutes. The oil which has been formed is purified as usual. The oil which in its pure condition is tough contains 13.3 per cent of N and 31.0 per cent of S whereas the calculation for the compound C'1H1sON2S2 yields 13.4 per cent of N and 30.8 per cent of S. I 1

heavy oil is precipitated which after the usual purification contains 10.7 per cent of N and 34.3 per cent of S.

Example 28.65 grams of methylxanthogenate dissolved in 100 cc. of methanol are mixed with a solution of 50 cc. of ethylene-imine and 30 cc. of

- glacial acetic acid in 600 cc. of water. After a oil is purified as usual. The tough mass which is obtained contains 14.4 per cent of N and 33.3

I per cent of 8, and is Supposed to be identical with the mass obtained according to Example 23.

Example 29 .-'I'he mixture is the same as that described in Example 28, however with omission of the glacial acetic acid. The mixture is allowed to stand for 10 hours at room temperature, after which time an oil has been formed at the bottom of the vessel. After usual purification a clear I tough oil containing 11.9 per cent of N and 34.2, per cent of S is obtained. The yield can be somewhat increased if, after the reaction is finished, the mixture is made acid by the addition of an optional acicl.

ethyleneimine.

4. A process ofproducing a thiazolidine compound which comprises reacting on a xanthogenate with a 1.2-halogen alkylamine.

5. ,A'process of producing a thiazolidine comgenate with a 1.2-halogen -alkylamine and the equivalent amount of caustic alkali or said 1.2- halogen alkylamine.

6. A process of producing a thiazolidine compound which comprises reacting on one molecular proportion of xanthogenate with one molecular proportion of a cyclic ethyleneimine salt.

7. A process of producing a thiazolidine compound which comprises reacting on-one molecular proportion of xanthogenate with one molecular proportion of a cyclic ethyleneimine salt and one molecular proportion of a cyclic ethyleneimine.

8. A process of. producing a thiazolidine com-- pound which" omprises reacting on a xanthogenate .with an imine selected irom the group consisting of ethylene-imine, ethylene-imine-2- carboxylic acid, ethylene-imine-sulionic acid,-

2-3-diacetylethylene-imlne, 2-octadecylethyleneimine, N-cyclohexanolethylene-imine, 2-phenylethylene-imine, ine. j

9. A process of producing a thiazolidine compound which comprises reacting'on a xanthogenate with one of the group consisting of broniethylamine, 'N --methyl bromethylamine, 'chlorpropylamine-1-2,

N-propyl-2-vinyl-ethylene-imbrombutylamine-2-8, 'N-butylchlorethyleamine.

chlorpropylamine 2 1.

dichlordiethrlamine, and the corresponding sulto esters.

10. A process of producing a thiazolidine compound which comprises reacting on a xanthogenate selected from the group consisting of methylxanthogenate, butylxanthogenate, octadecylxanthogenate, oleylxanthogenate, xanthogenates of sugars, xanthogenates of starch and cellulose xanthogenates with a cyclic ethyleneimine.

11. A process of producing a thiazolidine compound which comprises reacting on one molecular proportion of methylxanthogenate dissolved in methanol with a solution of one molecular proportion of ethylene-imine and the equivalent amount of glacial acetic acid.

12. A process of producing a thiazolidine compound which comprises reacting on one molecular proportion of bromethylamine bromhydrate and one molecular proportion of NaOH dissolved in water with one molecular proportion oi Namethylxanthogenate dissolved in methanol at 13. A process of producing a thiazolidine com-' pound which comprises reacting on one molecular proportion of methylxanthogenate dissolved in methanol with a solution of 2 molecular proportions of ethylene-imine and one molecular proportion of glacial acetic acid dissolved in water at 50 C.

14. Z-methoxy-2-mercaptothiazolidine having the formula sc1r,

C Hr-0O SH HN- H,

-15. 2-methoxy-2-mercaptothiazolidine containing aminoethyl and produced by the process claimed in claim '7.

16. A process of producing a thiazolidine com: pound whichcomprises reacting on a xanthogenate with a sulfo ester of 1.2-alkylolamines.

WALTER 

